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Expression of p53 and p53/47 are controlled by alternative mechanisms of messenger RNA translation initiation

Oncogene volume 25, pages 6936–6947 (2006)Cite this article

Abstract

P53 controls the growth and survival of cells by acting in response to a multitude of cellular stresses. It is, however, not yet fully understood how different p53 activation pathways result in either cell cycle arrest or apoptosis. We and others have described an N-terminally truncated p53 protein (p53/47) originating from a second translation initiation site in the p53 messenger RNA (mRNA), which can interact with p53 and impose altered stability and transactivation properties to p53 complexes. Here we show that cap-dependent and cap-independent mechanisms of initiation govern the translation of the p53 mRNA. Changes in synthesis of full-length p53 or p53/47 are regulated through distinct cell stress-induced pathways acting through separate regions of the p53 mRNA. We also show that some cytotoxic drugs require the presence of full-length p53 to induce apoptosis, whereas for others p53/47 is sufficient. This indicates that by harbouring alternative translation initiation sites, the p53 mRNA gives rise to different levels of the p53 isoforms which help to orchestrate the cell biological outcome of p53 activation in response to different types of cell stress. This sheds new light into the way p53 can integrate and differentiate a large multiplicity of changes in the cellular environment.

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Acknowledgements

This work was funded by the AICR, the AVENIR programme (INSERM) and by La Ligue Contre le Cancer. BV and ER were supported by grant NR8338-3/2005 from the Ministry of Health of the Czech Republic. MMC is supported by Grant SFRH/BD/16697/2004 from the Fundação para a Ciência e a Tecnologia of Portugal. The MLS-1765 cells were a kind gift from Dr Pierre Åman, Göteborg University, Sweden and we are thankful to Dr Anne Willis, Nottingham, UK for providing the hairpin construct, to Prof. Fabien Calvo for help with the MS and Dr Samia Mourah for help with designing primers. We are also thankful to Dr Y Yin for her earlier work on p53 translation. Flow Cytometry analysis was performed at the Imagery centre of the Technical Platform of IUH-IFR105.

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  1. M M Candeias and D J Powell: These authors contributed equally to this work

Authors and Affiliations

  1. Inserm U716, Institut de Génétique Moléculaire, Hôpital St Louis, Paris, France

    M M Candeias, D J Powell, S Apcher, K Bourougaa, H Bruzzoni-Giovanelli & R Fåhraeus

  2. Masaryk Memorial Cancer Institute, Brno, Czech Republic

    E Roubalova & B Vojtesek

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  1. M M Candeias
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  2. D J Powell
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  3. E Roubalova
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Correspondence to R Fåhraeus.

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Candeias, M., Powell, D., Roubalova, E. et al. Expression of p53 and p53/47 are controlled by alternative mechanisms of messenger RNA translation initiation. Oncogene 25, 6936–6947 (2006). https://doi.org/10.1038/sj.onc.1209996

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